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Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

ABSTRACT: Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

PROVIDER: PRJNA1165252 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30796927.fastq.gz	Fastqsanger.gz
	SRR30796928.fastq.gz	Fastqsanger.gz
	SRR30796929.fastq.gz	Fastqsanger.gz
	SRR30796930.fastq.gz	Fastqsanger.gz
	SRR30796931.fastq.gz	Fastqsanger.gz

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Similar Datasets

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

Project description:we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment.

2025-03-18 | PXD047045 | Pride

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer’s disease proteopathology for precision medication

Project description:Current amyloid beta-targeting approaches for Alzheimer’s disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.

2025-03-18 | GSE278032 | GEO

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer's disease proteopathology for precision medication.

Project description:Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.

| S-EPMC10690335 | biostudies-literature

Role of the histone methylase G9a in pancreatic carcinogenesis

Project description:Role of the histone methylase G9a in pancreatic carcinogenesis

| PRJNA627358 | ENA

Role of the histone methylase G9a in pancreatic carcinogenesis

Project description:Accumulating evidences propose the importance of epigenetic regulation in pancreatic carcinogenesis, but the mechanistic insights of a variety of histone modification process still remains to be elucidated. G9a functions as a transcriptional repressor via the methylating activity specific for histone H3 lysine9. We identified G9a as a critical factor in the development of murine pancreatic oncogenesis.

2020-11-03 | GSE149093 | GEO

Expression data from non-tumorous liver from chemically-induced hepatocellular carcinoma of wild-type or G9a deficient mice

Project description:Epigenetic gene regulation in various oncogenic pathways is currently an important focus of cancer research. Histone modification plays a pivotal role in human carcinogenesis, but the significance of histone modification in hepatocarcinogenesis remains unknown. We used microarrays to investigate the oncogenic gene regulation by histone methylase G9a in chemically-induced murine hepatocellular carcinioma model.

2021-01-27 | GSE147061 | GEO

G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain transition

Project description:AIM: We performed RNA-sequencing experiments seeking genes whose expression changed due to nerve injury. In addition, we wanted to test whether inhibition of the methyl transferase G9a/GLP, that methylates H3K9me2, could reverse those expression changes due to nerve ligation. G9a/GLP methylase was pharmacologically inhibited using UNC0638. METHOD: We generated cDNA libraries from RNA purified from DRGs obtained from Sham operated (4), SNL (4), and SNL plus UNC0638 (3) rats. We sequenced the cDNA libraries generating single end 50 bp reads on the illumina HiSeq 2500 platform. Sequencing reads were aligned to the rat genome rn4 using TopHat RESULTS: We were able to map 16876 genes, from which 2035 changed their expression values at least two fold when we compared SNL to Sham operated (pâ?¤ 0.01). There were 1205 upregulated and 832 down-regulated genes. Next, we focused on genes whose expression was either up or down-regulated 2 fold due to nerve ligation, and the values would be normalized to control level after G9a/GLP inhibito (UNC0638)r treatment. We identified 639 genes in our data set that behave this way We generated cDNA libraries from RNA purified from DRGs obtained from Sham operated (4), SNL (4), and SNL plus UNC0638 (3) rats. We sequenced the cDNA libraries generating single end 50 bp reads on the illumina HiSeq 2500 platform. Sequencing reads were aligned to the rat genome rn4 using TopHat

2015-11-02 | E-GEOD-59043 | biostudies-arrayexpress

Transcription profiling of mouse embryonic fibroblasts deleted for G9a reconstituted with empty vector (delta), wild type FLAG-G9a (WT), FLAG-G9a K165A (K165A) or FLAG-G9a H1093K catalytic mutant reveasl methylation of hMTase G9a on a histone-like site regulates protein complex assembly

Project description:Gene expression in eukaryotes is tightly linked to the methylation state of specific lysine residues within the N-terminal region of the core histone proteins. While the mechanisms connecting histone lysine methylation to effector protein recruitment and control of gene activity are increasingly well understood, it remains unknown whether non-histone chromatin proteins are targets for similar modification-recognition systems. Here we show that histone H3 and the H3 methyltransferase G9a share a conserved methylation motif that is both necessary and sufficient to mediate in vivo interaction with the potent epigenetic regulator Heterochromatin Protein 1 (HP1). As with H3, G9a-HP1 interaction is dependent on lysine methylation and can be reversed by adjacent phosphorylation. NMR analysis demonstrates that the HP1 chromodomain recognizes methyl-G9a through a binding mode similar to that used in recognition of methyl-H3, and that adjacent phosphorylation directly antagonizes G9a-HP1 interaction. In addition to uncovering the chromodomain as a generalized methyl-lysine binding module, these data identify histone-like modification cassettes (or âhistone mimicsâ) as an entirely new class of non-histone methylation targets, and directly demonstrate the relevance of the principles underlying the histone code to the regulation of non-histone proteins. Experiment Overall Design: Two independent Affymetrix gene expression microarray analyses were performed on samples from G9a-deleted MEFs reconstituted with empty vector (delta), wild type FLAG-G9a (WT), FLAG-G9a K165A (K165A) or FLAG-G9a H1093K catalytic mutant (H1093K).

2008-06-15 | E-GEOD-8011 | biostudies-arrayexpress

Identification of proteins stably associated with G9a/GLP (EHMT2/EHMT1) complex of histone methyltransferases

Project description:G9a (EHMT2) and the G9a-like protein GLP (EHMT1) form a stable G9a/GLP heterodimer in embryonic stem cells and function cooperatively to establish and maintain the abundant repressive H3K9me2 modification, in addition to modifying several non-histone proteins. The G9a-dependent H3K9me2 is implicated in lineage-specific gene silencing and covers large chromosomal domains. While the mechanism of H3K9me2maintenance by G9a/GLP is known, how new patterns of this modification are established is not well understood. With this in mind, we used FLAG affinity purification of G9a under two different stringency conditions (150 and 300 mM NaCl) coupled with mass spectrometry to identify proteins stably associated with G9a/GLP, which could serve as potential recruiters of the complex to unmodified chromatin.

2016-03-16 | PXD003466 | Pride

G9a is essential for epigenetic silencing of K+ channel genes in acute-to-chronic pain transition

Project description:AIM: We performed RNA-sequencing experiments seeking genes whose expression changed due to nerve injury. In addition, we wanted to test whether inhibition of the methyl transferase G9a/GLP, that methylates H3K9me2, could reverse those expression changes due to nerve ligation. G9a/GLP methylase was pharmacologically inhibited using UNC0638. METHOD: We generated cDNA libraries from RNA purified from DRGs obtained from Sham operated (4), SNL (4), and SNL plus UNC0638 (3) rats. We sequenced the cDNA libraries generating single end 50 bp reads on the illumina HiSeq 2500 platform. Sequencing reads were aligned to the rat genome rn4 using TopHat RESULTS: We were able to map 16876 genes, from which 2035 changed their expression values at least two fold when we compared SNL to Sham operated (p≤ 0.01). There were 1205 upregulated and 832 down-regulated genes. Next, we focused on genes whose expression was either up or down-regulated 2 fold due to nerve ligation, and the values would be normalized to control level after G9a/GLP inhibito (UNC0638)r treatment. We identified 639 genes in our data set that behave this way

2015-11-02 | GSE59043 | GEO

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